Objective-Recent research suggests a central role for CD40 ligand (CD40L) in atherogenesis. However, the relevant cellular source of this proinflammatory cytokine remains unknown. To test the hypothesis that CD40L expressed on hematopoietic cell types (eg, macrophages, lymphocytes, platelets) is crucial to atherogenesis, we performed bone marrow reconstitution experiments using low-density receptor-deficient (ldlr Ϫ/Ϫ ) and ldlr Ϫ/Ϫ /cd40l Ϫ/Ϫ compound-mutant mice. Methods and Results-As expected, systemic lack of CD40L in hypercholesterolemic ldlr Ϫ/Ϫ mice significantly reduced the development of atherosclerotic lesions in the aortic arch, aortic root, and abdominal aorta compared with ldlr